Ischemic Reperfusion Injury
Ischemic Reperfusion Injury (IRI) is cellular damage caused to a tissue or organ when blood supply returns to the tissue after a period of ischemia. The absence of blood oxygen and nutrients during the ischemic period creates a condition in which the restoration of circulation results in oxidative damage, including cellular dysfunction, apoptosis and necrosis.
IRI can occur in any body tissue as a result of inter alia surgery, wounds, trauma, obstructions, implantations and transplantations.
Delayed Graft Function
Delayed graft function (DGF) is an important risk factor in adversely affecting the outcome of organ transplants, including renal transplant such as deceased donor renal transplant (DDRT), particularly in a recipient of a kidney from an Expanded Criteria Donor (ECD) or from a Standard Criteria Donor (SCD) with prolonged cold ischemia time.
Analysis of over 138,000 cases in the UNOS Renal Transplant Registry database, revealed that long-term graft survival (>10 years) has remained unchanged despite improvements in short term acute rejection rates (Takada M, et al.; Transplantation. 1997 Dec. 15; 64(11):1520-5.). One of the major contributing factors to poorer long-term outcomes including poor graft survival identified in this retrospective review was DGF. DGF is defined by UNOS as the need for dialysis within the first seven days after transplantation. The etiology of DGF is not well understood but is undoubtedly multifactorial, in which IRI to the graft that directly results from the transplantation plays a central role. IRI is an antigen-independent process that is a major risk factor for development of chronic allograft dysfunction as demonstrated in animal models (Goes N, et al., Transplantation. 1995 27; 59(4):565-72; Kusaka M, et al., Transplantation. 1999 67(9):1255-61; Takada M, et al; Transplantation. 1997 64(11):1520-5). Ischemic conditions caused by reduced local blood flow to the kidneys during cold storage prior to transplantation followed by oxidative stress after the restoration of blood supply after the transplantation initiates a chain of events that can lead to acute tubular injury. Renal tubular cell dysfunction and apoptotic cell death are the hallmarks of this process (Oberbauer R, et al. J Am Soc Nephrol. 1999 10(9):2006-13; Giral-Classe M, et al. Kidney Int. 1998 54(3):972-8).
Due to the growing disparity between the numbers of candidates awaiting transplantation and available donor organs, the use of kidneys from Expanded Criteria Donors (ECD) has been increasing (Organ Procurement and Transplantation Network (OPTN), Scientific Registry of Transplant Recipients (SRTR). 2008 OPTN/SRTR Annual Report: Transplant Data 1998-2007 [Internet]. Richmond (Va.): Health Resources and Services Administration's Division of Transplantation (HRSA)/U.S. Department of Health & Human Services; 2009 Oct. 7 [cited 2010 April]).
U.S. Pat. Nos. 6,593,353; 6,982,277; 7,008,956 and 7,012,087 relate to the temporary inhibition of p53 for the treatment of cancer and other diseases and disorders.
U.S. Patent Application Publication No. 2006/0069056 to the assignee of the present application, is directed to short interfering p53 molecules and methods of use.
U.S. Pat. Nos. 7,910,566 and 8,148,342 to the assignee of the present application, relate to methods for treating acute kidney injury (AKI) and acute renal failure (ARF), respectively, with short interfering p53 molecules.
WO 2010/144336 to the assignee of the present application is directed to a method of treating a subject with chronic kidney disease (CKD) resulting from exposure to a recurring renal insult with a p53 inhibitor.
U.S. Patent Application Publication No. US 2010/0222409 and EP Patent No EP 2170403 to the assignee of the present application relate to a method of reducing Delayed Graft Function (DGF) in a recipient of a kidney transplant from a deceased donor using a double-stranded RNA compound for down-regulating the expression of a p53 gene.
PCT Patent Application No. PCT/US2013/059349, to the assignee of the present application, provides modified double-stranded nucleic acid compounds for down-regulating the expression of a p53 gene.
There remains an unmet need for a method of prevention or attenuation of ischemic reperfusion injury in native and donor organs.